Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter.
Cameron KN
,
Kolanos R
,
Solis E
,
Glennon RA
,
De Felice LJ
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: Bath salts is the street name for drug combinations that contain synthetic cathinone analogues, among them possibly mephedrone (MEPH) and certainly methylenedioxypyrovalerone (MDPV). In animal studies, cathinone and certain cathinone analogues release dopamine (DA), similar to the action of amphetamine (AMPH) and methamphetamine (METH). AMPH and METH act on the human DA transporter (hDAT); thus, we investigated MEPH and MDPV acting at hDAT.
EXPERIMENTAL APPROACH: We recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and exposed to: DA, METH, a known hDAT stimulant and DA releaser, MEPH, MDPV, MEPH + MDPV, or cocaine, a known hDAT inhibitor.
KEY RESULTS: DA, METH and MEPH induce an inward current (depolarizing) when the oocyte is held near the resting potential (-60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward (hyperpolarizing) current similar to cocaine, therefore acting as an inhibitory non-substrate blocker.
CONCLUSIONS AND IMPLICATIONS: Two components of bath salts, MEPH and MDPV, produce opposite effects at hDAT that are comparable with METH and cocaine, respectively. In our assay, MEPH is nearly as potent as METH; however, MDPV is much more potent than cocaine and its effect is longer lasting. When applied in combination, MEPH exhibits faster kinetics than MDPV, viz., the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts containing MEPH (or a similar drug) and MDPV might then be expected initially to release DA and subsequently prevent its reuptake via hDAT. Such combined action possibly underlies some of the reported effects of bath salts abuse.
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011, Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed
Banks,
Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys.
2011,
Pubmed
Baumann,
The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.
2012,
Pubmed
Bruns,
A fast activating presynaptic reuptake current during serotonergic transmission in identified neurons of Hirudo.
1993,
Pubmed
Carvelli,
Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission.
2008,
Pubmed
Coppola,
3,4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online.
2012,
Pubmed
Drug Enforcement Administration, Department of Justice,
Schedules of controlled substances: temporary placement of three synthetic cathinones in Schedule I. Final Order.
2011,
Pubmed
Glennon,
Methcathinone: a new and potent amphetamine-like agent.
1987,
Pubmed
Guptaroy,
Site-directed mutations near transmembrane domain 1 alter conformation and function of norepinephrine and dopamine transporters.
2011,
Pubmed
Hadlock,
4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse.
2011,
Pubmed
Han,
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs.
2006,
Pubmed
Howell,
Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys.
2007,
Pubmed
Huang,
Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats.
2012,
Pubmed
Ingram,
Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons.
2002,
Pubmed
Iwamoto,
Na+, Cl-, and pH dependence of the human choline transporter (hCHT) in Xenopus oocytes: the proton inactivation hypothesis of hCHT in synaptic vesicles.
2006,
Pubmed
,
Xenbase
Kahlig,
Amphetamine induces dopamine efflux through a dopamine transporter channel.
2005,
Pubmed
Kalix,
Further evidence for an amphetamine-like mechanism of action of the alkaloid cathinone.
1986,
Pubmed
Kalix,
Cathinone, a natural amphetamine.
1992,
Pubmed
Kehr,
Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats.
2011,
Pubmed
Kelly,
Cathinone derivatives: a review of their chemistry, pharmacology and toxicology.
2011,
Pubmed
López-Arnau,
Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone.
2012,
Pubmed
Machaca,
Asymmetrical distribution of Ca-activated Cl channels in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Martínez-Clemente,
Interaction of mephedrone with dopamine and serotonin targets in rats.
2012,
Pubmed
Meltzer,
1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors.
2006,
Pubmed
Motbey,
Mephedrone (4-methylmethcathinone, 'meow'): acute behavioural effects and distribution of Fos expression in adolescent rats.
2012,
Pubmed
Negus,
Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.
2007,
Pubmed
Rodriguez-Menchaca,
S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis.
2012,
Pubmed
,
Xenbase
Rothman,
Therapeutic potential of monoamine transporter substrates.
2006,
Pubmed
Sellings,
Segregation of amphetamine reward and locomotor stimulation between nucleus accumbens medial shell and core.
2003,
Pubmed
Simmler,
Pharmacological characterization of designer cathinones in vitro.
2013,
Pubmed
Sonders,
Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants.
1997,
Pubmed
,
Xenbase
Spiller,
Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States.
2011,
Pubmed
Sulzer,
Mechanisms of neurotransmitter release by amphetamines: a review.
2005,
Pubmed
Sulzer,
How addictive drugs disrupt presynaptic dopamine neurotransmission.
2011,
Pubmed
Williams,
The dopamine transporter: a vigilant border control for psychostimulant action.
2006,
Pubmed
